Thanks to medical advances, spinal muscular atrophy (SMA) no longer casts a long shadow over young lives. Patients with this hereditary disease once faced an inevitable wasting of muscles and an early death. However, treatments that make up for the genetic defect behind SMA mean that even children with severe disease can now look forward to adulthood.
Yet these new prospects may also mean new health issues. “We’ve noticed a large proportion of children and adults with SMA have fatty liver (steatosis) on ultrasound scanning,” said Crystal Yeo, Principal Investigator of the Translational Neuromuscular Medicine Laboratory at the A*STAR Institute of Molecular and Cell Biology (A*STAR IMCB), who directed this research. “As children with SMA live longer, the possibility of liver problems might become more apparent, as fatty liver may, in some cases, lead to inflammation, scarring and even liver failure.”
Yeo, who is also a neurologist specialising in neuromuscular diseases, explained that SMA is caused by a mutation in the gene SMN1, causing a lack of survival motor neuron (SMN) protein in muscle nerve cells. But SMN isn’t found solely in such cells; it’s present throughout the body and involved in RNA transcription.
To confirm if a lack of SMN could also be behind these liver issues, Yeo and her team worked with collaborators from A*STAR IMCB and the National University of Singapore; Harvard University and Boston Children’s Hospital, US; and the University of Aberdeen, Scotland, in a multinational study of clinical data from patients with SMA and patient-derived stem cell models.
“We used stem cells from the patients to create liver-like cells (iHeps) in the lab to directly study how SMA affects liver function,” said Yeo. “Compared to healthy cells, SMA iHeps showed fat buildup and impaired energy production, as well as issues with clotting blood, processing fats and sugars, and breaking down drugs.”
Using CRISPR gene editing tools, the team then corrected the iHeps’ SMN1 defects, restoring normal SMN protein levels. This reversed the previous steatosis and metabolic issues, confirming that an SMN deficiency directly caused the liver problems. Further proteomics analyses also revealed proteins and molecular pathways affected in SMA liver, such as FMO3, a key enzyme in drug metabolism.
To the team’s surprise, neither disease severity, treatment status nor age affected the presence of SMA fatty liver, suggesting a more widespread issue than anticipated. In addition, even iHeps that carried just one defective SMN1 copy—reflecting people who carry only one defective SMA gene and live without symptoms (SMA carriers)—continued to have the same issues.
“Our study suggests that doctors should also monitor liver function in SMA patients, not just the nervous system,” said Yeo. “As some SMA treatments rely on a healthy liver and can cause mild liver toxicity, this could help prevent serious complications.”
Yeo added that further studies were needed to understand exactly how SMN loss causes fatty liver and affects other organs. “This is also important for other disorders with similar liver issues like amyotrophic lateral sclerosis (ALS), and for the estimated one in 50 people worldwide who carry one faulty SMN1 gene,” said Yeo.
The A*STAR-affiliated researcher contributing to this research is from the A*STAR Institute of Molecular and Cell Biology (A*STAR IMCB).
